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Diabetes therapy 13(1), 57-73 (2022). doi:10.1007/s13300-021-01179-8, Published by Springer Healthcare Communications, New York, NY [u.a.]

Using pooled data from the REALI European database, we evaluated the impact of previous basal insulin (BI) type on real-life effectiveness and safety of switching to insulin glargine 300 U/ml (Gla-300) in people with suboptimally controlled type 2 diabetes.Patient-level data were pooled from 11 prospective, open-label, 24-week studies. Participants were classified according to the type of prior BI. Of the 4463 participants, 1282 (28.7%) were pre-treated with neutral protamine Hagedorn (NPH) insulin and 2899 (65.0%) with BI analogues (BIAs), and 282 (6.3%) had undetermined prior BI.There were no meaningful differences in baseline characteristics between subgroups, except for a higher prevalence of diabetic neuropathy in the NPH subgroup (21.6% versus 7.8% with BIAs). Mean ± standard deviation haemoglobin A1c (HbA1c) decreased from 8.73 ± 1.15% and 8.35 ± 0.95% at baseline to 7.71 ± 1.09% and 7.82 ± 1.06% at week 24 in the NPH and BIA subgroups, respectively. Least squares (LS) mean change in HbA1c was - 0.85% (95% confidence interval - 0.94 to - 0.77) in NPH subgroup and - 0.70% (- 0.77 to - 0.64) in BIA subgroup, with a LS mean absolute difference between subgroups of 0.16 (0.06-0.26; p = 0.002). Gla-300 mean daily dose was slightly increased at week 24 by 0.07 U/kg/day (approximately 6 U/day) in both subgroups. Incidences of symptomatic and severe hypoglycaemia were low, without body weight change.Irrespective of previous BI therapy (NPH insulin or BIAs), switching to Gla-300 improved glycaemic control without weight gain and with low symptomatic and severe hypoglycaemia incidences. However, a slightly greater glucose-lowering effectiveness was observed in people pre-treated with NPH insulin.

Diabetes therapy 12(4), 1073-1097 (2021). doi:10.1007/s13300-021-01030-0, Published by Springer Healthcare Communications, New York, NY [u.a.]

The effectiveness of Gla-300 in PWT2D switching from NPH is not widely documented. REALI database combines individual data from 14 European studies in T2D. We analyzed data from PWT2D uncontrolled on prior basal insulin (BI) , 1282 switching from NPH and 2899 from other non-NPH BIs (mainly glargine 100 U/mL, 67%) to Gla-300. In the NPH group, mean±SD age was 63±9.4 years, BMI 32.5±5.8 kg/m2, and median diabetes duration 12 years. The majority previously used biguanides (71%) , followed by sulfonylureas (20%) , and dipeptidyl peptidase 4 inhibitors (18%) . HbA1c markedly improved after a 24-week Gla-300 therapy (Figure 1A) . Mean±SD fasting plasma glucose (FPG) decreased from 188.8±55.9 mg/dL at Baseline to 143.3±45.5 at Week 24. Gla-300 was started at a mean dose of 29.4 U/day and titrated up to 35.6 at Week 24, with no body weight (BW) change. In the non-NPH BI group, baseline characteristics were comparable to those in the NPH group, except for higher baseline HbA1c and FPG in the latter. Figure 1B illustrates HbA1c improvement in the non-NPH BI group, at a mean Gla-300 starting dose of 35.4 U/day increasing to 41.7 at Week 24, with no BW change. Hypoglycemia was similarly low in both groups. This analysis shows that PWT2D, previously uncontrolled on BI, benefited from switching to Gla-300 in terms of HbA1c improvement, and this was especially observed in those previously treated with NPH. Disclosure D.Müller-wieland: Advisory Panel; Amarin Corporation, Amgen Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Daiichi Sankyo, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Amarin Corporation, Amgen Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Daiichi Sankyo, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. N.Freemantle: Consultant; Novo Nordisk, Research Support; Aimmune, ALK-Abelló A/S, Allergan, AstraZeneca, Ipsen Biopharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Sanofi, Vertex Pharmaceuticals Incorporated, Speaker's Bureau; Abbott. R.C.Bonadonna: Advisory Panel; Sanofi, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly, Novo Nordisk. C.Mauquoi: None. G.Bigot: None. M.Bonnemaire: Employee; Sanofi. P.Gourdy: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Mundipharma, Novo Nordisk, Sanofi, Sanofi, Speaker's Bureau; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk. D.Mauricio: Advisory Panel; Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi, Speaker's Bureau; Almirall, S.A., Esteve, Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi. Funding Sanofi

Diabetes therapy 12(4), 1159-1174 (2021). doi:10.1007/s13300-021-01031-z, Published by Springer Healthcare Communications, New York, NY [u.a.]

IntroductionType 2 diabetes mellitus (T2DM) is a common and heterogeneous disease. Using advanced analytic approaches to explore real-world data may identify different disease characteristics, responses to treatment and progression patterns. Insulin glargine 300 units/mL (Gla-300) is a second-generation basal insulin analogue with preserved glucose-lowering efficacy but reduced risk of hypoglycaemia. The purpose of the REALI pooled analysis described in this paper is to advance the understanding of the effectiveness and real-world safety of Gla-300 based on a large European patient database of postmarketing interventional and observational studies.Methods and analysisIn the current round of pooling, REALI will include data from up to 10 000 subjects with diabetes mellitus (mostly T2DM) from 20 European countries. Outcomes of interest include change from baseline to week 24 in haemoglobin A1c, fasting plasma glucose, self-measured plasma glucose, body weight, insulin dose, incidence and rate of any-time-of-the-day and nocturnal hypoglycaemia. The data pool is being investigated using two complementary methodologies: a conventional descriptive, univariate and multivariable prognostic analysis; and a data-mining approach using subgroup discovery to identify phenotypic clusters of patients who are highly associated with the outcome of interest. By mid-2019, deidentified data of 7584 patients were included in the REALI database, with a further expected increase in patient number in 2020 as a result of pooling additional studies.Ethics and disseminationThe proposed study does not involve collection of primary data. Moreover, all individual study protocols were approved by independent local ethics committees, and all study participants provided written informed consent. Furthermore, patient data is deidentified before inclusion in the REALI database. Hence, there is no requirement for ethical approval. Results will be disseminated via peer-reviewed publications and presentations at international congresses as data are analysed.

Despite an increasing number of patients with type 2 diabetes (T2D) in the older population, clinical evidence for different therapeutic strategies in the elderly is poor. Therefore, we used the REALI pooled database, which includes a large number of studies conducted in different European countries to evaluate the impact of initiating insulin glargine 300 U/mL (Gla-300) in older patients with T2D. Pooled efficacy and safety analyses of data from three interventional and five observational studies (pooled treated patients, n=5806) were performed on three age groups of patients: Disclosure R.C. Bonadonna: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Sanofi-Aventis. Speaker's Bureau; Self; Eli Lilly and Company, Sanofi-Aventis. D. Mauricio: Advisory Panel; Self; Merck Sharp & Dohme Corp., Sanofi. Speaker's Bureau; Self; Almirall, S.A., Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Urgo Medical. D. Müller-Wieland: Advisory Panel; Self; Amgen Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis Deutschland GmbH. Speaker's Bureau; Self; Amgen Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis Deutschland GmbH. N. Freemantle: Advisory Panel; Self; Sanofi. Research Support; Self; Akcea Therapeutics, Allergan, AstraZeneca, Ipsen Biopharmaceuticals, Inc., Sanofi, Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Sanofi. G. Bigot: None. C. Mauquoi: None. A. Ciocca: Employee; Self; Sanofi. M. Bonnemaire: Employee; Self; Sanofi. P. Gourdy: Advisory Panel; Self; AstraZeneca. Board Member; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis, Servier. Speaker's Bureau; Self; Abbott, Amgen Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis, Servier. Funding Sanofi

Chronic kidney disease is common in patients with type 2 diabetes (T2D) and has an impact on the choice and dosage of T2D therapies, as well as on the individual’s glycemic target and the risk of hypoglycemia. We evaluated the impact of initiating insulin glargine 300 U/mL (Gla-300) in patients with T2D according to eGFR level, using the REALI pooled database which includes several Gla-300 studies conducted in different European countries. Pooled efficacy and safety analysis of data from three interventional studies was performed on patients treated with Gla-300 having an eGFR at baseline either ≥60 (n=923) or Disclosure D. Mauricio: Advisory Panel; Self; Merck Sharp & Dohme Corp., Sanofi. Speaker's Bureau; Self; Almirall, S.A., Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Urgo Medical. P. Gourdy: Advisory Panel; Self; AstraZeneca. Board Member; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis, Servier. Speaker's Bureau; Self; Abbott, Amgen Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis, Servier. R.C. Bonadonna: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Sanofi-Aventis. Speaker's Bureau; Self; Eli Lilly and Company, Sanofi-Aventis. N. Freemantle: Advisory Panel; Self; Sanofi. Research Support; Self; Akcea Therapeutics, Allergan, AstraZeneca, Ipsen Biopharmaceuticals, Inc., Sanofi, Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Sanofi. G. Bigot: None. C. Mauquoi: None. A. Ciocca: Employee; Self; Sanofi. M. Bonnemaire: Employee; Self; Sanofi. D. Müller-Wieland: Advisory Panel; Self; Amgen Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis Deutschland GmbH. Speaker's Bureau; Self; Amgen Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis Deutschland GmbH. Funding Sanofi

Background The purpose of this study was to determine the cardiac safety and clinical activity of trastuzumab and bevacizumab with docetaxel after epirubicin with cyclophosphamide (EC) in patients with HER2-positive locally advanced breast cancer (LABC) or pathologic stage 3 breast cancer (PS3BC). Patients and Methods Patients received every 3 week treatment with 4 cycles of EC (90/600 mg/m2) followed by 4 cycles of docetaxel (100 mg/m2). Targeted therapy with standard-dose trastuzumab with bevacizumab 15 mg/kg was given for a total of 1 year. Coprimary end points were (1) rate of cardiac events (CEs) in all patients defined as clinical congestive heart failure with a significant decrease in left ventricular ejection fraction or cardiac deaths; and (2) pathologic complete response (pCR) in breast and nodes in the neoadjuvant cohort. An independent cardiac review panel determined whether criteria for a CE were met. Results A total of 105 patients were accrued, 76 with LABC treated with neoadjuvant therapy and 29 with PS3BC treated with adjuvant therapy. Median follow-up was 59.2 months. Among 99 evaluable patients for cardiac safety, 4 (4%; 95% confidence interval [CI], 1.1%-10.0%) met CE criteria. The pCR percentage in LABC patients was 46% (95% CI, 34%-59%). Five-year recurrence-free survival (RFS) and overall survival (OS) for all patients was 79.9% and 90.8%, respectively. Conclusion The regimen met predefined criteria for activity of interest with an acceptable rate of CEs. Although the pCR percentage was comparable with chemotherapy regimens with trastuzumab alone the high RFS and OS are of interest in these high-risk populations.